Photodynamic therapy (PDT) is an evolving modality for the treatment of cancer. In order for PDT to be effective, a number of events must occur. Initially a sensitizer must localize somewhat selectively into neoplastic tissue (usually within a 24-28 h period). Irradiation of the target site with light at a wavelength corresponding to an absorption band of the sensitizer results in a photodynamic action which produces powerful oxidants including singlet oxygen. These highly reactive species then begin to destroy the integrity of the cell and the tumor vasculature, leading eventually to cell death. Although Photofrin II has been the most studied photosensitizer to date for PDT, there are disadvantages associated with its use. These include a poor absorption in the therapeutically useful red region of the visible spectrum, a persistent skin photosensitivity which has been noticed during clinical trials and a complex chemical composition. This latter property has hindered the interpretation of pharmacologic and photobiologic data, consequently, little is known regarding the events which lead to cell necrosis. New sensitizers are therefore being developed which appear to overcome the disadvantages of Photofrin II. This Program Project attempts to study some of the important aspects of PDT with a view to better understanding how PDT works. In Project 1 (Structure -Activity Relationships for Sensitizers in PDT) we will develop new sensitizers with better spectroscopic characteristics than current sensitizers and will attempt to relate biological activity of sensitizer-PDT to sensitizer structure. Project 2 (Effect of Delivery System on PDT) will assess PDT from the point of view of the delivery system (emulsion, liposome, inclusion complex) used to administer sensitizers. Project 3 (Determinants of Tumor Localization) will study the interaction of new photosensitizers and new delivery systems with tumor cells in vitro and in vivo while Project 4 (Biologic Response to PDT) will concentrate on studies, both in vitro and in vivo, involving the effect of PDT on the endothelial cell. Finally, a study of the effect of PDT on normal tissue will be evaluated using three clinically relevant sites.